Cognition Therapeutics, Inc. (CogRx) is developing CT1812, a disease-modifying drug for Alzheimer?s disease. CT1812 is the first highly brain penetrant selective sigma-2 receptor antagonist small molecule. This drug candidate selectively displaces amyloid-? oligomers bound to neuronal receptors at synapses and protects synapses from toxic oligomer effects, clearing oligomers from the brain into the cerebrospinal fluid. When administered once daily for 28 days to mild to moderate AD patients, CT1812 significantly increases CSF concentration of A?Os, increases plasma concentrations of lipids and metabolites, and reduces concentrations of synaptic degeneration markers in AD patient CSF, consistent with the disease-modifying and synaptoprotective mechanism of action established in preclinical studies. No other therapeutic currently in development selectively targets the most toxic form of the A? protein ? oligomers (A?Os) and has demonstrated selective clearance of A?O into CSF in AD patients. No other AD drug candidate has demonstrated normalization of dysregulated protein and lipid/metabolite analytes in AD patient biofluids or reported reduction of synaptic damage markers in AD patients as much, and as rapidly, as CT1812. We hypothesize that the effects of oligomer displacement and clearance on cognitive function wil l be detectable in symptomatic patients, and the effect on disease modification will be detectable in presymptomatic patients. CogRx discovered CT1812, its mechanism of action and the role of the sigma-2 receptor complex in AD. No other group is pursuing this mechanism of action for Alzheimer?s disease treatment. CT1812 has been demonstrated to be safe and well tolerated in healthy volunteers and mild-to moderate AD patients in placebo-controlled Phase 1b/2a trials. Adverse events were predominantly mild and included headache and GI disturbances. Two doses of CT1812 are currently being evaluated in follow-on safety trials in mild to moderate AD patients (Q.D. for 6 months, MMSE 18-26). These same two doses will be tested in early AD patients (MMSE 20-30) in the current trial, with treatment duration extended to 18 months. This project proposes to conduct a randomized, double-blind, placebo-controlled, Phase 2 trial to evaluate the safety and tolerability of two doses of CT1812 in patients with early AD (MMSE 20-30, corresponding to FDA late stage 2 to early stage 4) given q.d. over 18 months. This trial will determine whether CT1812 beneficially affects cognition as measured by CDR-SB and other secondary cognitive measures, as well as measuring the impact of CT1812 on biomarkers of target engagement (CSF concentrations of A? oligomers and synaptic degeneration proteins) and disease modification (CSF concentrations of total tau and NfL, serum NfL as well as hippocampal and whole brain volume change by MRI). Completion of this study in early AD patients will inform the design and methods of the subsequent long term disease modification Phase 3 trials with CT1812.